Apoptosis plays a variety of roles, including the elimination of abnormal cells such as tumor cells. Apoptosis can be activated by two pathways: an intrinsic pathway involving mitochondrial dysfunction and an extrinsic pathway via death receptor stimulation. Death receptors are cell surface receptors in the tumor necrosis factor receptor (TNFR) superfamily and include TNF-R1, CD95 (APO-1, Fas), TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1; DR4) and TRAIL-R2 (DR5). Death receptors comprise a cytoplasmic death domain and binding of their respective ligands leads to activation. TNF-related apopotosis-inducing ligand (TRAIL) is a ligand for DR4 and DR5. Ligand binding leads to association with the Fas-Associated Death Domain (FADD). This adaptor recruits caspase-8 and caspase-10 to form a Death-Inducing Signaling Complex (DISC), leading to effector caspase activation and cell death.
TNF-R1 and CD95 activation has been shown to efficiently kill tumor cells. Thus, cancer therapies have been implemented that attempt to induce apoptosis of tumor cells by activating these death receptors using ligands and agonist antibodies. However, such efforts have been limited by the severe side effects that have been observed. On the other hand, activation of DR4 and DR5 has been shown to selectively eliminate cancer cells without life-threatening toxicity, and the ligand has been shown to have synergistic effects with other chemotherapeutics in killing tumor cells without additional side effects.